Rapid developments in genomics research have increased expectations for identifying vulnerability genes involved in the pathophysiology of functional gastrointestinal disorders. However, the study of genetics in irritable bowel syndrome (IBS) is in its infancy and has been hampered by a focus on clinical phenotype association studies. Furthermore, current research strategies have largely overlooked sex of the subject as an important variable despite the fact that sex can modify both penetrance and expressivity of a wide variety of complex traits. The overall goal of this proposal is to provide new information on sex-specific genetic influences involved in the pathophysiology of IBS pain. The findings should have significant implications for translational research and the development of personalized treatments, thereby improving health care for IBS patients. The candidate has a long-standing interest in sex-related biological differences and her current research has focused on altered central nervous system (CNS) functions in IBS pain. The candidate's long-term goals include becoming established in the field of genomics research. The career development plan will focus on developing a broad-based and in depth understanding of genetics and intermediate neurobiological phenotypes as they relate to sex-specific models of IBS pain through didactic and mentored training. The candidate will be mentored by Dr. Emeran Mayer, Director of the UCLA Center for Neurobiology of Stress (a translational research center co-funded by NIDDK, the Office of Women's Health and NCCAM) and will have access to its wealth of resources. In addition, the candidate has enlisted as co-mentors UCLA faculty members with expertise in genetics and systems biology (Dr. Steve Horvath), genetic association studies (Dr. Jeanette Papp), phenomics (Dr. Robert Bilder), fMRI methodology, including imaging genetics approaches (Dr. Susan Bookheimer), and psychophysiological mechanisms of pain (Dr. Bruce Naliboff). The proposed research plan is designed to identify common and sexually dimorphic genes involved in the pathophysiology of IBS pain (Aim 1), and to investigate sex differences in the association between genetic variations and altered CNS function related to pain modulation in IBS patients using both fMRI and psychophysiological measures (Aim 2). Genes contributing to visceral pain sensitivity will be identified using a new experimental design to examine sex- specific alterations in gene expression during a visceral pain challenge (Project 1) and using an advanced modeling technique to investigate sex-specific genetic architecture and association with visceral pain sensitivity (Project 2). The influence of sexually dimorphic genes on pain-related brain network activity and descending pain inhibition will be examined using fMRI (Project 3) and the nociceptive lower limb flexion reflex (Project 4). Together, the proposed studies will enhance knowledge of genetic and neural pathways influencing pain sensitivity in IBS and enable the candidate to propose new testable hypotheses regarding mechanisms of IBS pain, in particular regarding differential treatment approaches based on pathophysiology and sex differences. PUBLIC HEALTH RELEVANCE: The long-term goal of this proposal is to improve treatment strategies for patients with irritable bowel syndrome (IBS), by providing a better understanding of sex differences in the genetic contribution to IBS pathophysiology. Such differences have important implications for tailoring treatments to individuals and are expected to stimulate the field of personalized medicine.